This is a translational research proposal to investigate the pathogenesis of Hepatitis C Virus (HCV)-related mixed cryoglobulinemia (MC). The K08 award will assist me in realizing my goal of becoming an independent physician-scientist researching viral immunopathogenesis at an academic medical center. Ultimately, I would like to bridge bench and bedside, applying knowledge gained from my studies towards the treatment of HCV MC. Currently, I am Chief Clinical Scholar at Rockefeller University, and I am enrolled in the Clinical Scholars Master's Degree Program, which will provide me with formal didactic instruction in biostatistics, clinical trial design and biocomputing during the mentored phase of the K08 award. My surroundings at the Center for the Study of Hepatitis C, Rockefeller University, New York- Presbyterian Hospital and Bellevue Hospital will provide me with ample scientific and clinical resources to pursue my research. As part of my research career development plan, I have formed a K08 Advisory Committee, comprised of clinicians and basic scientists, which will meet quarterly and formally review my research progress. This will also provide me with crucial career guidance. With the assistance of my clinical mentors at New York-Presbyterian Hospital, I plan to enroll patients in a study designed to determine how chronic HCV infection elicits the production of monoclonal autoantibodies. MC affects up to 50% of HCV patients, causing a small-vessel vasculitis. HCV MC is clearly a risk factor for the development of B cell non- Hodgkin lymphoma. In HCV MC, the cryoglobulins usually contain a monoclonal immunoglobulin (Ig) M rheumatoid factor (RF) associated with polyclonal IgG. I have already found that HCV+MC+ patients have monoclonal expansions of hypermutated, lgM+?+CD21lowCD27+ B cells which exhibit highly restricted usage of RF-encoding genes. In collaboration with my clinical and scientific mentors, I have designed experiments to determine the antigenic specificity of the IgMs expressed by these B cells, testing the hypothesis that the HCV structural protein, E2, in the form of an immune complex, interacts with the B cell receptor, causing the selective proliferation of E2-specific clones. Relevance: An understanding of how HCV causes B cell dysregulation could lead to improved treatments for HCV MC. Moreover, these studies could further our understanding of viral-induced autoimmunity and malignancy.